Synthetic efforts toward the synthesis of octalactins

Article abstract of DOI:10.1016/j.tet.2008.04.026

Octalactin B was synthesized from the commercially available methyl-3-butenoate and isobutyraldehyde, using enantioselective allyl- and crotyltitanations to control the stereogenic centers at C3, C4, C7, C8, and C13. Moreover, the two other key-step react

Full text of DOI:10.1016/j.tet.2008.04.026

Tetrahedron 64 (2008) 5703–5710
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthetic efforts toward the synthesis of octalactins
, ,
y
b
a,
*
Minh-Thu Dinh a, Samir Bouzbouz a , Jean-Louis Peglion , Janine Cossy
*
´
a Laboratoire de Chimie Organique associe´ au CNRS, ESPCI, 10 rue Vauquelin, 75231 Paris Cedex 05, France
b Laboratoire Servier, 11 rue des Moulineaux, 92150 Suresnes, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Octalactin B was synthesized from the commercially available methyl-3-butenoate and isobutyraldehyde,
using enantioselective allyl- and crotyltitanations to control the stereogenic centers at C3, C4, C7, C8, and
C13. Moreover, the two other key-step reactions are a cross-metathesis reaction and a lactonization,
using the effective anhydride MNBA, to build up the eight-membered ring lactone.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 15 November 2007
Received in revised form 4 April 2008
Accepted 8 April 2008
Available online 11 April 2008
1. Introduction
and a cross-metathesis (CM) to construct the C5–C6 bond. Com-
pound of type A would be synthesized from an aldol condensation
Octalactin A was isolated from the marine bacterium Strepto-
myces sp. in 1991,1 together with the related compound, octalactin
B (Fig. 1). The structure of octalactin A was established by X-ray
crystallographic analysis and the absolute configuration of the
stereogenic centers in octalactin A and octalactin B were estab-
lished independently by synthesis.2,3 In addition, octalactin A ex-
hibits potent cytotoxicity in tests with B-16-F10 murine melanoma
and HCT-116 human colon tumor cell lines, whereas octalactin B
was completely inactive. However, it has been shown that octa-
lactin B can be transformed easily to octalactin A by a one-step
epoxidation. Because of their structural complexity and their in-
teresting biological properties, octalactins have solicited consider-
able interest among organic chemists and three total syntheses,2,4
two formal syntheses as well as the preparation of several frag-
ments of octalactins have been reported.5 An excellent review by
Shiina has been published recently on the synthesis of octalactins A
and B.6 Here, we would like to report two approaches for obtaining
octalactins.
between a ketone of type B and an aldehyde of type C. Compound B
would be obtained from aldehyde of type D, which would be the
result of a CM between hydroxyester 2 and acrolein. An enantio-
selective crotylmetalation applied to 10 would allow the access to 2
(Scheme 1).
The unstable ester-aldehyde 10 was prepared by ozonolysis of
the commercially available methyl-3-butenoate (1) (O3, CH2Cl2,
ꢀ78 ꢁC then Me2S, MeOH/CH2Cl2, rt) and treated directly with the
highly face selective crotyltitanium complex (R,R)Ti-I (Et2O,
ꢀ78 ꢁC) to afford the desired hydroxyester 2 in 79% overall yield
based on (R,R)Ti-I (2 steps), with a diastereomeric excess superior
to 95% and with an enantiomeric excess (ee) of 94%.7 In order to
obtain aldehyde 5, that would allow the introduction of the ster-
eogenic centers at C7 and C8, a CM between 2 and acrolein
(4.7 equiv) was achieved using Hoveyda-Grubbs catalyst ([Ru]-I
(7.2 mol %), CH2Cl2, rt, 20 h) and the unsaturated aldehyde 3 was
formed in 86% isolated yield (conversion of 2¼85%). After pro-
tection of 3 (TBSOTf, 2,6-lutidine, CH2Cl2, ꢀ78 ꢁC), followed by an
hydrogenation step (Pd/C 10%, AcOEt, 1 h), aldehyde 5 was isolated
in quantitative yield and treated directly with the highly face se-
lective crotyltitanium complex (S,S)Ti-I (Et2O, ꢀ78 ꢁC). As after
purification by flash chromatography, the homoallylic alcohol could
not be separated from the Taddol, resulting from the (S,S)Ti-I
complex, the mixture was treated with TBSOTf (2,6-lutidine,
2. First approach
At first, we have envisaged the synthesis of octalactin B from the
linear polyhydroxyester A, with the purpose of examinating the
regioselectivity of the possible lactonizations under kinetic or
thermodynamic control. In order to synthesize fragment A, the key
steps would be enantioselective crotylmetalations to control all the
stereogenic centers, an aldol reaction to built up the C10–C11 bond,
O
O
HO
HO
O
O
9
OH
13
O
O
9
OH
13
3
3
7
7
O
* Corresponding authors. Tel.: þ33 1 40 79 44 29; fax: þ33 1 40 79 46 60.
E-mail address: janine.cossy@espci.fr (J. Cossy).
(-)-Octalactin B
(-)-Octalactin A
y
Present address: UMR 6014, Laboratoire de Chimie Pharmaceutique, UFR
´
Medecine et Pharmacie, CNRS, 22Bd Gambetta, Rouen, France.
Figure 1.
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.04.026

5704
M.-T. Dinh et al. / Tetrahedron 64 (2008) 5703–5710
O
(imidazole, CH2Cl2). After purification by flash chromatography on
silica gel, the protected homoallylic alcohol 10 was isolated in 75%
yield with an ee superior to 95%. The transformation of 10 to the
desired hydroxyaldehyde 11 was realized by ozonolysis (O3, CH2Cl2,
ꢀ78 ꢁC then PPh3, rt, quantitative) (Scheme 3).
HO
O
O
O
OH
(-)-Octalactin B
1) (R,R)Ti-II (1.3 equiv)
Et2O, -78 °C, 3.5 h
O
OTBS
OH
3
OH
7
O
9
OH
13
11
10
H
MeO
2) TBSCl, Imidazole, CH2Cl2, rt
A
9
75%
10
ee > 95%
O3
O
O
OR
OR
OR
O
O
OR
Ph
CH2Cl2
+
MeO
MeO
H
quant.
Ph
O
O
-78 °C;
PPh3, rt
Ti
O
Ph
B
C
O
Ph
O
OR
O
O
OTBS
O
5
(R,R)Ti-II
MeO
MeO
H
H
H
6
11
D
E
Scheme 3.
O
OH
O
O
Having compounds 8 and 11 in hand, an aldolisation between
these two compounds was performed. The generation of the (Z)-
titanium enolate from 8 (TiCl4, i-Pr2NEt, CH2Cl2, ꢀ78 ꢁC, 1.5 h) fol-
lowed by the addition of 11 (9 equiv, ꢀ78 ꢁC to rt, 1.5 h), led to the
aldol product 12 in 90% with a good diastereoselectivity (superior
to 95%). The required unsaturated ketone 13, precursor of the
compound of type A, was prepared in a one-pot reaction by
mesylation (MsCl, Et3N, CH2Cl2, 0 ꢁC) followed by addition of DBU
at rt. After this two-step sequence, enone 13 was isolated in 50%
yield. In order to obtain the polyhydroxyester A, compound 13
has to be deprotected. At first, 13 was treated with tetrabuty-
lammonium fluoride (TBAF) (THF, rt, 3 days), but unfortunately,
under these conditions, the only product that could be isolated
was diene 14 in 16% yield. Furthermore, when 13 was treated
with HF$Py (THF, rt), tetrahydropyranone 15, which comes from
an intramolecular 1,4-addition of the hydroxy group at C7 to the
enone, was formed and isolated as an inseparable mixture of
diastereomers (1:1) in 61% yield (Scheme 4). Due to these results,
a second approach to octalactins was considered from aldehyde 5
(Scheme 4).
MeO
H
1'
2
Scheme 1.
CH2Cl2, ꢀ78 ꢁC) to furnish, after purification by flash chromato-
graphy on silica gel, the desired compound 6, which corresponds to
the C1–C9 fragment (76% yield). Compound 6 was then trans-
formed to ethylketone 8 via alcohol 7 in 3 steps. After oxidative
cleavage of the double bond [OsO4, NMO, acetone/H2O (2.5:1) then
NaIO4], ethylmagnesium bromide was directly added to the non-
purified obtained aldehyde to produce the corresponding alcohol 7
in 60% yield. Its oxidation using the Dess–Martin periodinane
(DMP) (CH2Cl2, rt) afforded the desired ethylketone 8 (95% yield)
(Scheme 2).
In parallel, the optically active hydroxyaldehyde 11, which rep-
resents the C11–C15 fragment of octalactins, was prepared from
isobutyraldehyde 9. The addition of the allyltitanium complex
(R,R)Ti-II (Et2O, ꢀ78 ꢁC) to isobutyraldehyde 9 led to the desired
homoallylic alcohol,8 which was protected by using TBSCl
O3, CH2Cl2, -78 °C; Me2S
CH2Cl2/MeOH (2/1),rt
(R,R)Ti-I (0.3 equiv)
Et2O, -78 °C, 3.5 h
O
OH
O
O
OH
O
[Ru]-I (7.2 mol %),
[1']
MeO
H
MeO
MeO
Acrolein (4.7 equiv),
CH2Cl2,rt, 20 h
86% (conversion: 85%)
1
2
3
79%, 2 steps
ee = 94%
TBSOTf, 2,6-lutidine
CH2Cl2, -78 °C
quantitative
de > 95%
H2, Pd/C10%
(2.5 mol %)
AcOEt, 1 h
1) (S,S)Ti-I (1.3 equiv)
Et2O,-78 °C, 3.5 h
O
O
OTBS
OTBS
OTBS
O
O
OTBS
O
MeO
H
MeO
MeO
H
quantitative
2) TBSOTf, 2,6-lutidine,
CH2Cl2, -78 °C
5
4
6
ee, de > 95%
76%
Ph
Ph
O
Ph
N
N
Ph
O
O
1) OsO4(0.1 equiv),
Mes
Mes
Ti
O
Ti
Cl
O
NMO then NaIO4
Ru
O
60%
Cl
Acetone/H2O (2.5/1)
O
O
Ph
Ph
OiPr
Ph
Ph
(R,R)Ti-I
2) EtMgBr, THF, 0 °C
(S,S)Ti-I
[Ru]-I
Dess-Martin
OTBS
OH
O
OTBS
OTBSO
O
OTBS
Periodinane
95%
MeO
MeO
8
7 : dr = 1/1
Scheme 2.

M.-T. Dinh et al. / Tetrahedron 64 (2008) 5703–5710
5705
O
OTBS
90%
OTBSO
vinyllithium reagent F was envisaged from the protected hydroxy-
aldehyde 11, which was previously obtained (Scheme 5).
MeO
As previously, aldehyde 5 was treated with the highly face
selective crotyltitanium complex (S,S)Ti-I (Et2O, ꢀ78 ꢁC) and then
transformed to the corresponding carboxylic acid. As after puri-
fication by flash chromatography, the homoallylic alcohol could
not be separated from the Taddol resulting from the (S,S)Ti-I
complex, the mixture was directly treated with LiOH$H2O (THF/
MeOH 1:1) to furnish the carboxylic acid 16, which was isolated
with an overall yield of 70% from aldehyde 5. The obtained seco-
acid 16 was cyclized to form the eight-membered ring lactone 17
in 90% yield using the effective anhydride, 2-methyl-6-nitro-
benzoic anhydride (MNBA) (1.1 equiv), and DMAP (6 equiv) in
toluene at rt. After oxidative cleavage of the double bond in 17
(OsO4, NMO then NaIO4), aldehyde 18 was isolated quantitatively
(Scheme 6).9
8
TiCl4, i-Pr2NEt, CH2Cl2, -78 °C, 1.5 h;
OTBS
O
,-78 °C to rt, 1.5 h
H
11
(9 equiv)
O
OTBS
OTBSO
OH OTBS
MeO
12
1) MsCl, Et3N, CH2Cl2, 0 °C
2) DBU, rt
50%
OTBS
O
OTBSO
OTBS
MeO
13
1) (S,S)Ti-I
O
OTBS
OH
O
OTBS
O
(1.3 equiv)
Et2O, -78 °C
TBAF (3 equiv)
THF, rt, 3 days
O
OH
OH
O
HO
MeO
H
13
2) LiOH·H2O
THF/MeOH
(1/1)
16
MeO
5
16%
12
NO2 O2N
O
14
70%
13
90%
O
O
HO
MNBA (1.1 equiv)
DMAP (6 equiv)
Toluene, rt
HF Py
61%
O
OH
O
MeO
O
O
O
O
OsO4 (6 mol %), NMO
Acetone/H2O (2.5/1)
then NaIO4
15
Scheme 4.
TBSO
TBSO
O
O
quantitative
H
3. Second approach
17
18
Scheme 6.
In the second approach, octalactins would be obtained by
a chemoselective addition of a vinyllithium reagent of type F on an
aldehyde-lactone of type G. In this approach, the stereogenic cen-
ters would be also controlled by enantioselective crotylmetalations
and the lactone of type G would be derived from the hydroxyacid H,
which would be prepared from aldehyde 4. The synthesis of the
In parallel, the vinyliodide 21, precursor of the vinyllithium re-
agent of type F, was prepared from 11 in three steps. After trans-
formation of 11 to dibromide 19, by treatment of 11 with PPh3/CBr4
(CH2Cl2, yield 85%), this compound was transformed to the acety-
lenic compound 20 (n-BuLi, MeI, THF, ꢀ78 ꢁC) in 99% yield. The
hydrozirconation of 20 (Cp2ZrHCl, benzene, 40 ꢁC) followed by
iodolysis (I2, THF, 0 ꢁC) furnished the desired vinyliodide 21
(Scheme 7).
O
HO
O
O
OH
PPh3, CBr4
CH2Cl2
OTBS
O
OTBS
Br
(-)-Octalactin B
H
85%
Br
99%
11
19
O
n-BuLi, MeI
THF, -78 °C
RO
O
OR
OR
O
O
1) Cp2ZrHCl
2) I2, THF, 0 °C
OTBS
OTBS
+
Li
H
I
26%
G
F
20
21
Scheme 7.
O
OH
OR
OR
After a halogen-metal exchange (t-BuLi, Et2O, ꢀ78 ꢁC), the de-
sired vinyllithium reagent prepared from vinyliodide 21 was added
to aldehyde-lactone 18 at ꢀ78 ꢁC to afford the desired allylic alco-
hol 22 in 50% yield without any noticeable diastereoselectivity,
which has no consequence on the synthesis of octalactins as the
hydroxy group at C9 has to be transformed to a ketone. This allylic
alcohol 22 was then transformed to octalactin B in two steps. After
a Dess–Martin oxidation (CH2Cl2, rt), followed by a deprotection
(HF$Py, THF, rt), octalactin B was isolated in 68% yield. The optical
H
HO
11
H
O
O
MeO
H
4
Scheme 5.

5706
M.-T. Dinh et al. / Tetrahedron 64 (2008) 5703–5710
rotation of the synthetic octalactin B revealed to be ꢀ37 (c 0.7,
CHCl3), which is close to the optical rotation of the isolated natural
product [ꢀ12.3 (c 5.6, CHCl3)], compared to the optical rotations of
the previously synthesized octalactin B,2–4 which are approxi-
mately 10 times larger than that reported for the natural product
itself.1 Unfortunately, we could not have access to the racemic
octalactin B and could not verify the optical purity by HPLC. It is
worth noting that octalactin B can be transformed easily to octa-
lactin A by epoxidation4 [t-BuO2H, VO(acac)2] (Scheme 8).
Purification of the residue by flash chromatography on silica gel
(petroleum ether/Et2O 8:2) afforded product 2 (1.2 g, 79%) as
20
a yellow liquid. Rf¼0.60 (petroleum ether/AcOEt 6:4). [
1.0, CHCl3). IR (neat) 3450, 2940, 1740 cmꢀ1
CDCl3)
a
]
D
þ25.2 (c
;
1H NMR (400 MHz,
d
5.72 (ddd, J¼16.5, 10.9, 8.0 Hz, 1H), 5.03 (dd, J¼16.5, 1.3 Hz,
1H), 5.01 (dd, J¼8.0, 1.3 Hz, 1H), 3.75 (m, 1H), 3.62 (s, 3H), 2.69 (br s,
1H), 2.40 (d, J¼3.0 Hz, 1H), 2.38 (d, J¼7.5 Hz, 1H), 2.22 (m, 1H), 1.00
(d, J¼6.7 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d 173.2 (s), 139.4 (d),
115.8 (t), 71.0 (d), 51.5 (q), 43.2 (d), 38.6 (t), 15.6 (q); MS (EI) m/z:
158 (Mþ, 0), 127 (10), 103 (100), 71 (76); HRMS calcd: 181.0841
[(MþNa)þ, M¼C8H14O3]; found: 181.0843.
O
TBSO
OTBS
O
O
I
4.2.2. (þ)-3-Hydroxy-4-methyl-7-oxohept-5-enoic acid
methylester (3)
To a solution of 2 (145 mg, 0.91 mmol) in CH2Cl2 (8 mL) were
added Hoveyda-Grubbs catalyst [Ru]-I (41 mg, 0.065 mmol) and
+
H
18
21
t-BuLi (2 equiv)
Et2O, -78 °C
50%
acrolein (280 mL, 4.23 mmol) and the resulting mixture was stirred
at rt overnight. After concentration, the crude oil was purified
by flash chromatography on silica gel (petroleum ether/Et2O 1:1)
to afford 3 (126.3 mg, 86% corrected yield for 85% conversion) as
O
TBSO
O
OH
OTBS
20
a brown oil. Rf¼0.4 (petroleum ether/AcOEt 6:4). [
a
]
þ18.9 (c
D
0.4, CHCl3). IR (neat) 3437, 2921, 2851, 1729, 1686 cmꢀ1
(400 MHz, CDCl3)
1H), 6.08 (ddd, J¼15.8, 7.9, 1.1 Hz, 1H), 3.99 (dtapp, J¼12.4, 3.5 Hz,
1H), 3.64 (s, 3H), 3.30 (d, J¼3.5 Hz, 1H), 2.50 (m, 1H), 2.43 (d,
J¼3.4 Hz, 1H), 2.40 (d, J¼8.3 Hz, 1H), 1.11 (d, J¼7.1 Hz, 3H); 13C
;
1H NMR
22
d
9.46 (d, J¼7.9 Hz, 1H), 6.86 (dd, J¼15.8, 7.9 Hz,
1) Dess-Martin, CH2Cl2, rt
2) HF.Py (3 equiv)
THF, rt
68%
O
NMR (100 MHz, CDCl3)
d 194.0 (d), 173.0 (s), 159.0 (d), 133.3
HO
O
O
OH
(d), 70.7 (d), 51.9 (q), 42.2 (d), 39.0 (t), 15.7 (q); MS (EI) m/z: 186
(Mþ, 0), 155 [(MꢀOMe)þ, 2], 137 [(MꢀOMeꢀH2O)þ, 2], 109
[(MꢀOMeꢀH2OꢀCHO)þ, 4], 103 (26), 84 (100), 71 (42), 55 (40).
(-)-Octalactin B
Scheme 8.
4.2.3. (ꢀ)-3-[(tert-Butyldimethylsilyl)oxy]-4-methyl-7-oxohept-
5-enoic acid methylester (4)
Octalactin B was obtained in 14.5% overall yield in 12 steps from
methyl-3-butenoate (1) by using highly enantioselective crotylti-
tanation of aldehydes and a CM reaction. This synthesis represents
one of the shortest syntheses of octalactin B.
To a solution of 3 (172.6 mg, 0.93 mmol) in CH2Cl2 (9 mL) at
ꢀ78 ꢁC were added 2,6-lutidine (0.8 mL, 6.8 mmol) and TBSOTf
(1 mL, 4.3 mmol). The mixture was stirred for 2 h at ꢀ78 ꢁC and
then hydrolyzed with a saturated NaHCO3 aqueous solution
(50 mL). The organic layer was extracted with CH2Cl2 (3ꢂ50 mL),
dried over MgSO4, filtered, and concentrated under vacuum to af-
ford crude product. Purification on silica gel (petroleum ether/
4. Experimental section
4.1. General
AcOEt 8:2) afforded 4 (278 mg, quantitative) as a yellow oil. Rf¼0.3
20
(petroleum ether/AcOEt 9:1). [
a
]
ꢀ1.0 (c 1.4, CHCl3). IR (neat)
D
2940, 1740, 1690 cmꢀ1 1H NMR (400 MHz, CDCl3)
; d 9.42 (d,
Diethyl ether (Et2O) and tetrahydrofuran (THF) were distilled
prior to use. All other reagents and solvents were obtained from
commercial sources and used without further purification.
Reactions were routinely carried out under an atmosphere of dry
argon with magnetic stirring.
J¼7.9 Hz, 1H), 6.75 (dd, J¼15.8, 7.9 Hz, 1H), 6.04 (ddd, J¼15.8, 7.9,
1.1 Hz, 1H), 4.12 (dtapp, J¼9.4, 3.4 Hz, 1H), 3.55 (s, 3H), 2.56 (m, 1H),
2.38 (dd, J¼15.2, 6.7 Hz, 1H), 2.27 (dd, J¼15.2, 6.0 Hz, 1H), 1.06 (d,
J¼7.1 Hz, 3H), 0.82 (s, 9H), 0.01 (s, 6H); 13C NMR (100 MHz, CDCl3)
d
194.0 (d), 171.7 (s), 159.0 (d), 133.3 (d), 71.9 (d), 51.6 (q), 42.7 (d),
4.2. First approach of octalactins
40.0 (t), 25.7 (3q), 17.9 (s), 15.2 (q), ꢀ3.6 (q), ꢀ4.7 (q); MS (EI) m/z:
300 (Mþ, 0), 285 (1), 269 (9), 243 (41), 217 (49), 183 (56), 141 (54),
89 (81), 73 (100).
4.2.1. (þ)-3-Hydroxy-4-methylhex-5-enoic acid methylester (2)
A solution of methyl-3-butenoate (3 g, 30 mmol) in CH2Cl2
(60 mL) was stirred under O3 bubbling at ꢀ78 ꢁC. After 2.5 h, MeOH
(30 mL) and Me2S (30 mL, 40.5 mmol) were added and the result-
ing mixture was stirred for 3.5 h at rt. After concentration, aldehyde
10 was obtained as a colorless oil and directly engaged to the next
4.2.4. (þ)-3-[(tert-Butyldimethylsilyl)oxy]-4-methyl-
7-oxoheptanoic acid methylester (5)
A mixture of 4 (1.66 g, 5.52 mmol), Pd/C (10%) (17 mg, 0.16 mmol)
in AcOEt (20 mL) was stirred under a hydrogen atmosphere for 1 h at
rt then filtered over Celite. The filtrate was concentrated under
step. To
a suspension of complex (R,R)-TaddolTiCpCl (5 g,
11.5 mmol) in Et2O (160 mL) at ꢀ40 ꢁC, was added crotylmagne-
sium chloride (45 mL, 0.35 M in THF, 15.7 mmol). The mixture was
stirred at 0 ꢁC for 1.5 h, then cooled at ꢀ78 ꢁC and the freshly
obtained aldehyde 10 was added to the mixture. After 3.5 h of
stirring at ꢀ78 ꢁC, the mixture was hydrolyzed with water (100 mL)
with strong stirring overnight at rt. The mixture was then filtered
over Celite and the organic layer was extracted with Et2O
(3ꢂ100 mL). The combined organic layers were washed with brine,
dried over MgSO4, filtered, and concentrated under vacuum.
vacuum to afford 5 (1.67 g, quantitative) as a colorless oil. Rf¼0.7
20
(petroleum ether/AcOEt 8:2). [
a
]
þ20.1 (c 0.8, CHCl3). IR (neat)
D
2920, 1730 cmꢀ1; 1H NMR (400 MHz, CDCl3)
d
9.72 (t, J¼1.5 Hz, 1H),
4.05 (ddd, J¼7.5, 5.0, 3.6 Hz, 1H), 3.61 (s, 3H), 2.46–2.39 (m, 2H),
2.39–2.32 (m, 2H), 1.75–1.52 (m, 2H), 1.33 (m, 1H), 0.85 (d, J¼6.7 Hz,
3H), 0.80 (s, 9H), 0.00 (s, 3H), ꢀ0.04 (s, 3H); 13C NMR (100 MHz,
CDCl3) d 202.0 (d),172.4 (s), 72.6 (d), 51.4 (q), 41.8 (t), 38.3 (d), 38.1 (t),
25.6 (3q), 24.2 (t), 17.9 (s), 14.2 (q), ꢀ4.7 (q), ꢀ4.9 (q); MS (EI) m/z:
302 (Mþ, 0), 245 [(Mꢀt-Bu)þ, 46], 217 [(Mꢀt-BuꢀCHO)þ, 39], 203

M.-T. Dinh et al. / Tetrahedron 64 (2008) 5703–5710
5707
[(Mꢀt-BuꢀHOꢀMe)þ, 9], 185 [(Mꢀt-BuꢀCHOꢀOMe)þ, 23], 171
(400 MHz, CDCl3)
d
4.02 (dtapp, J¼11.0, 5.5 Hz, 1H), 3.68 (tappd,
[(Mꢀt-BuꢀCHOꢀOMeꢀCH2)þ, 98], 89 (100), 73 (76), 59 (33).
J¼7.7, 5.5 Hz, 1H), 3.58 (s, 3H), 3.37 (td, J¼10.8, 3.8 Hz, 1H), 2.31
(dd, J¼19.8, 11.0 Hz, 1H), 2.24 (dd, J¼19.8, 5.5 Hz, 1H), 1.62–1.00
(m, 9H), 0.88 (t, J¼10.0 Hz, 3H), 0.82 (s, 9H), 0.81 (d, J¼6.5 Hz,
3H), 0.77 (s, 9H), 0.72 (d, J¼6.7 Hz, 3H), 0.00 (2s, 6H), ꢀ0.03 (s,
4.2.5. (þ)-3,7-Bis-[(tert-butyldimethylsilyl)oxy]-4,8-dimethyl-
dec-9-enoic acid methylester (6)
To
a
suspension of complex (R,R)-TaddolTiCpCl (611 mg,
3H), ꢀ0.07 (s, 3H); 13C NMR (100 MHz, CDCl3)
d 172.9 (s), 75.9
0.93 mmol) in Et2O (16 mL) at ꢀ40 ꢁC, was added crotylmagnesium
chloride (2.8 mL, 0.35 M in THF, 0.98 mmol). The resulting mixture
was stirred for 1.5 h at 0 ꢁC then cooled to ꢀ78 ꢁC and aldehyde 5
(216 mg, 0.71 mmol) was added to the reaction mixture. After 3.5 h
of stirring at ꢀ78 ꢁC, the mixture was hydrolyzed with water
(20 mL) with strong stirring for 1 h at rt. The mixture was then
filtered over Celite and the organic layer was extracted with AcOEt
(3ꢂ50 mL). The combined organic layers were washed with brine,
dried over MgSO4, filtered, and concentrated under vacuum. The
residue was dissolved in CH2Cl2 (8 mL) and cooled to ꢀ78 ꢁC. To this
solution was added 2,6-lutidine (0.1 mL, 0.86 mmol) and TBSOTf
(0.2 mL, 0.87 mmol) and the resulting mixture was stirred for 1.5 h
at ꢀ78 ꢁC. After hydrolysis with a saturated NaHCO3 aqueous so-
lution (50 mL), the organic layer was extracted with CH2Cl2
(3ꢂ50 mL), dried over MgSO4, filtered, and concentrated under
vacuum. The residue was purified by flash chromatography on silica
(d), 75.2 (d), 73.1 (d), 51.5 (q), 42.9 (d), 39.5 (d), 37.9 (t), 32.0 (t),
29.7 (t), 27.5 (t), 25.9 (3q), 25.7 (3q), 18.0 (s), 17.9 (s), 13.8 (q), 12.5
(q), 9.4 (q), ꢀ4.2 (2q), ꢀ4.5 (q), ꢀ4.9 (q).
4.2.7. (þ)-3,7-Bis[(tert-butyldimethylsilyl)oxy]-4,8-dimethyl-
9-oxoundecanoic acid methylester (8)
To a solution of 6 (348 mg, 0.68 mmol) in CH2Cl2 (15 mL) was
added Dess–Martin periodinane (842 mg,1.98 mmol). The resulting
mixture was stirred for 2.5 h at rt and then hydrolyzed with
a mixture of Na2S2O3 (1.5 M)/NaHCO3 (40 mL/40 mL) aqueous so-
lution. After extraction with CH2Cl2 (3ꢂ100 mL), the combined or-
ganic layers were dried over MgSO4, filtered, and concentrated
under vacuum. The crude product was purified by flash chroma-
tography on silica gel (petroleum ether/AcOEt/Et3N 94:5:1) to af-
ford ketone 7 (329 mg, 95%) as a colorless oil. Rf¼0.7 (petroleum
20
ether/AcOEt 9:1). [
a
]
þ32.6 (c 1.0, CHCl3). IR (neat) 2940, 1740,
D
gel (petroleum ether/AcOEt 95:5) to afford 6 (157.8 mg, 76% in 2
1720 cmꢀ1
;
1H NMR (400 MHz, CDCl3)
d
4.06 (dtapp, J¼8.1, 4.0 Hz,
20
steps) as a colorless oil. Rf¼0.7 (petroleum ether/AcOEt 95:5). [
a
]
1H), 3.90 (dtapp, J¼8.1, 4.0 Hz, 1H), 3.62 (s, 3H), 2.68 (quint, J¼7.1 Hz,
1H), 2.45 (q, J¼7.0 Hz, 2H), 2.34 (dd, J¼9.8, 4.3 Hz, 1H), 2.29 (dd,
J¼14.7, 4.3 Hz, 1H), 1.60–1.10 (m, 5H), 0.99 (d, J¼7.1 Hz, 3H), 0.96 (d,
J¼7.1 Hz, 3H), 0.91 (d, J¼6.7 Hz, 3H), 0.82 (s, 9H), 0.81 (s, 9H), 0.00
(2s, 6H), ꢀ0.03 (s, 3H), ꢀ0.08 (s, 3H); 13C NMR (100 MHz, CDCl3)
D
þ42.7 (c 1.1, CHCl3). IR (neat) 2950, 1740 cmꢀ1; 1H NMR (400 MHz,
CDCl3)
d 5.74 (m, 1H), 4.98–4.90 (m, 2H), 4.05 (m, 1H), 3.61 (s, 3H),
3.45 (m,1H), 2.38–2.21 (m, 3H),1.60–1.00 (m, 5H), 0.94 (d, J¼6.7 Hz,
3H), 0.84 (d, J¼6.7 Hz, 3H), 0.84 (s, 9H), 0.80 (s, 9H), 0.00 (s, 12H);
13C NMR (100 MHz, CDCl3)
d
172.9 (s), 140.9 (d), 114.3 (t), 76.0 (d),
d 214.3 (s), 172.8 (s), 73.8 (d), 73.2 (d), 51.4 (q), 50.1 (d), 39.6 (d), 38.0
73.0 (d), 51.4 (q), 43.1 (d), 39.4 (d), 37.9 (t), 31.6 (t), 28.6 (t), 25.9
(3q), 25.7 (3q), 18.1 (s), 17.9 (s), 15.2 (q), 13.9 (q), ꢀ4.2 (q), ꢀ4.4 (q),
ꢀ4.6 (q), ꢀ4.9 (q); MS (EI) m/z: 472 (Mþ, 0), 457 (3), 441
[(MꢀOMe)þ, 1], 415 (62), 385 [(MꢀOMeꢀt-Bu)þ, 28], 283 (30), 185
(65), 171 (56), 159 (38), 89 (50), 73 (100).
(t), 37.0 (t), 31.7 (t), 29.7 (t), 25.9 (3q), 25.8 (3q), 22.7 (s),17.9 (s),13.8
(q), 12.6 (q), 7.3 (q), ꢀ4.5 (q), ꢀ4.6 (q), ꢀ4.9 (2q); MS (EI) m/z: 502
(Mþ, 0), 445 [(MꢀOMeꢀMe)þ, 21], 359 [(MꢀOMeꢀ2ꢂt-Bu)þ,78],
199 (100), 171 (40), 75 (48).
4.2.8. 3,7,13-Tris[(tert-butyldimethylsilyl)oxy]-11-hydroxy-
4.2.6. 3,7-Bis[(tert-butyldimethylsilyl)oxy]-9-hydroxy-
4,8-dimethylundecanoic acid methylester (7)
4,8,10,14-tetramethyl-9-oxopentadecanoic acid methylester (12)
To a solution of 7 (348 mg, 1 M in CH2Cl2, 0.68 mmol) in CH2Cl2
(7 mL) were added TiCl4 (0.86 mL, 0.86 mmol) and Hu¨nig’s base
(0.20 mL, 1.15 mmol). The resulting dark brown mixture was stirred
for 3 h at ꢀ78 ꢁC and then aldehyde 11 (200 mg, 0.98 mmol) was
introduced as a 0.2 M CH2Cl2 solution. After 2 h of stirring at ꢀ78 ꢁC,
the mixture was hydrolyzed with a saturated NH4Cl aqueous so-
lution (50 mL). After extraction with AcOEt (3ꢂ50 mL), the com-
bined organic layers were dried over MgSO4, filtered, and
concentrated under vacuum. The residue was purified by flash
chromatography on silica gel (petroleum ether/AcOEt/Et3N 94:5:1)
To a solution of 5 (63.5 mg, 0.134 mmol) in a mixture of ace-
tone/water (2.5 mL/1 mL) were added NMO (0.7 g, 0.59 mmol)
and OsO4 (3.5 mg, 0.0138 mmol). The mixture was stirred for 2 h
at rt, then NaIO4 (120 mg, 0.56 mmol) was added and the mixture
was stirred 2 h. After filtration, the organic layer was extracted
with AcOEt (3ꢂ50 mL), dried over MgSO4, filtered, and concen-
trated under vacuum. The residue was dissolved in THF (15 mL)
and the solution was cooled at 0 ꢁC. Ethylmagnesium bromide
(50 mL, 3 M in Et2O, 0.14 mmol) was added and the mixture was
stirred for 20 min at 0 ꢁC. After hydrolysis with a saturated NH4Cl
aqueous solution (50 mL), the organic layer was extracted with
AcOEt (3ꢂ50 mL), dried over MgSO4, filtered, and concentrated
under vacuum. The residue was purified by flash chromatography
on silica gel (petroleum ether/AcOEt 95:5) to afford alcohol 7
(40.4 mg, 60% in 3 steps) as a diastereomeric mixture (1:1) and as
and product 12 (448 mg, 90%) was isolated as a colorless oil. Rf¼0.6
20
(petroleum ether/AcOEt 9:1). [
a
]
þ17.2 (c 0.6, CHCl3). IR (neat)
D
3510, 2960, 1740, 1700 cmꢀ1
J¼10.8 Hz, 1H), 4.09 (dtapp, J¼11.4, 5.2 Hz, 1H), 3.95 (dtapp, J¼10.5,
5.3 Hz, 1H), 3.75 (m, 1H), 3.66 (s, 3H), 3.03 (br s, 1H), 2.92 (tapp
; d 4.20 (d,
1H NMR (400 MHz, CDCl3)
,
J¼9.3 Hz, 1H), 2.56 (qd, J¼9.5, 4.0 Hz, 1H), 2.40 (dd, J¼19.4, 11.4 Hz,
1H), 2.30 (dd, J¼19.4, 5.2 Hz, 1H), 1.83 (m, 1H), 1.60–1.40 (m, 5H),
1.30–1.20 (m, 2H),1.16 (d, J¼7.3 Hz, 3H), 0.97 (d, J¼6.9 Hz, 3H), 0.90–
0.80 (m, 36H), 0.09 (s, 3H), 0.08 (s, 3H), 0.06 (s, 3H), 0.05 (s, 3H), 0.04
a
colorless oil. For the two diastereomers: IR (neat) 3800,
1890 cmꢀ1. MS (EI) m/z: 504 (Mþ, 0), 417 [(MꢀOMeꢀt-Bu)þ, 5],
359 [(MꢀOMeꢀ2ꢂt-Bu)þ, 4], 257 (54), 201 (31), 171 (28), 149
(37), 89 (49), 73 (100). Diastereomer 7a: Rf¼0.6 (petroleum ether/
(s, 3H), ꢀ0.00 (s, 3H); 13C NMR (100 MHz, CDCl3)
d 218.2 (s), 172.7
AcOEt 9:1). 1H NMR (400 MHz, CDCl3)
d
4.00 (m, 1H), 3.81 (tapp
,
(s), 73.8 (d), 73.5 (d), 73.2 (d), 66.8 (d), 51.9 (d), 51.4 (q), 48.9 (t), 39.6
(d), 38.0 (t), 35.5 (t), 33.4 (d), 31.4 (t), 26.1 (t), 25.9 (3q), 25.8 (3q),
25.7 (3q),18.4 (s and q),18.1 (s),17.9 (s),17.0 (q),13.8 (q),12.4 (q), 9.8
(q), ꢀ4.2 (2q), ꢀ4.5 (q), ꢀ4.6 (q), ꢀ4.7 (q), ꢀ4.9 (q). HRMS calcd:
755.5110 [(MþNa)þ, M¼C38H80O7Si3]; found: 755.5116.
J¼6.4 Hz, 1H), 3.62 (td, J¼6.8, 2.6 Hz, 1H), 3.57 (s, 3H), 3.50 (br s,
1H), 2.30 (dd, J¼14.7, 8.3 Hz, 1H), 2.20 (dd, J¼14.7, 4.3 Hz, 1H),
1.60–1.30 (m, 4H), 1.30–1.00 (m, 4H), 0.88 (d, J¼7.1 Hz, 3H), 0.84
(d, J¼7.5 Hz, 3H), 0.80–0.75 (m, 21H), 0.00 (s, 3H), ꢀ0.02 (s, 3H),
ꢀ0.04 (s, 3H), ꢀ0.08 (s, 3H); 13C NMR (100 MHz, CDCl3)
d 172.6
(s), 79.2 (d), 72.8 (d), 71.9 (d), 51.5 (q), 39.4 (d), 38.1 (t), 37.8 (d),
33.2 (t), 28.5 (t), 27.4 (t), 25.8 (3q), 25.7 (3q), 17.9 (2s), 14.3 (q),
11.2 (q), 10.5 (q), ꢀ4.2 (q), ꢀ4.6 (q), ꢀ4.7 (q), ꢀ4.8 (q). Dia-
stereomer 7b: Rf¼0.5 (petroleum ether/AcOEt 9:1). 1H NMR
4.2.9. (þ)-3,7,13-Tris[(tert-butyldimethylsilyl)oxy]-11-hydroxy-
4,8,10,14-tetramethyl-9-oxopentadecanoic acid methylester (13)
To a stirring solution of 12 (234 mg, 0.32 mmol) in CH2Cl2 (5 mL)
at 0 ꢁC were added Et3N (50
mL, 0.26 mmol) and MsCl (30 mL,

5708
M.-T. Dinh et al. / Tetrahedron 64 (2008) 5703–5710
0.36 mmol). After 3 h of stirring at 0 ꢁC, the mixture was hydrolyzed
with a saturated aqueous NH4Cl (50 mL) solution and the organic
layer was extracted with CH2Cl2 (3ꢂ50 mL), dried, filtered, and
concentrated under vacuum. The residue was dissolved in CH2Cl2
(4 mL) and DBU (24 mL, 0.16 mmol) was added. The resulting mix-
ture was stirred for 2 h at rt, concentrated, and the residue was
purified by preparative TLC (petroleum ether/AcOEt 95:5) to afford
to stir for 3.5 h at ꢀ78 ꢁC. After hydrolysis with water (20 mL) with
a strong stirring for 2 h at rt, the mixture was filtered over Celite
and the organic layer was extracted with AcOEt (3ꢂ100 mL). The
combined organic layers were washed with brine, dried over
MgSO4, filtered, and concentrated under vacuum. The residue was
dissolved in a mixture of THF/MeOH 1:1 (2 mL/2 mL) and LiOH
(1.12 mL, 5 M in water, 5.64 mmol) was added. After 5 h of stirring
at rt, the mixture was hydrolyzed with a saturated NH4Cl aqueous
solution (50 mL). The organic layer was extracted with AcOEt
(3ꢂ50 mL), washed with brine, dried over MgSO4, filtered, and
concentrated under vacuum. The crude product was purified by
flash chromatography on silica gel (petroleum ether/AcOEt 7:3) to
13 (112 mg, 49%) as a colorless oil. Rf¼0.9 (petroleum ether/AcOEt
20
9:1). [
a
]
þ30.7 (c 1.1, CHCl3). IR (neat) 2950, 1740, 1660 cmꢀ1; 1H
D
NMR (400 MHz, CDCl3)
d 6.69 (m, 1H), 4.05 (m, 1H), 3.96 (m, 1H),
3.61 (s, 3H), 3.55 (m, 1H), 3.36 (m, 1H), 2.38–2.22 (m, 4H), 1.66 (m,
1H), 1.50–0.90 (m, 5H), 1.00–0.60 (m, 42H), 0.05-ꢀ0.20 (m, 18H);
13C NMR (100 MHz, CDCl3)
d
204.9 (s), 172.8 (s), 139.9 (d), 138.4 (s),
afford acid 16 (448 mg, 70% in 2 steps) as a colorless oil. Rf¼0.6
20
75.9 (d), 73.8 (d), 73.1 (d), 51.4 (q), 43.3 (d), 39.8 (d), 37.9 (t), 33.5
(t), 33.4 (d), 31.8 (t), 25.8 (3q), 25.7 (3q), 25.6 (3q), 25.6 (t), 18.0
(2s), 18.0 (q), 17.9 (s), 17.7 (q), 14.0 (q), 13.8 (q), 11.9 (q), ꢀ5.0 (2q),
ꢀ4.9 (2q), ꢀ4.6 (q), ꢀ4.5 (q). HRMS calcd: 737.5004 [(MþNa)þ,
M¼C38H78O6Si3]; found: 737.5011.
(petroleum ether/AcOEt 6:4). [
a]
þ5.4 (c 1.2, CHCl3). 1H NMR
D
(400 MHz, CDCl3)
d
6.40 (br s, 1H), 5.71 (ddd, J¼16.6, 10.9, 8.3 Hz,
1H), 5.05 (d, J¼16.6 Hz, 1H), 5.03 (dd, J¼8.3, 1.2 Hz, 1H), 4.08 (ddd,
J¼6.0, 4.3, 4.1 Hz,1H), 3.35 (dd, J¼11.3, 6.0 Hz,1H), 2.36 (d, J¼6.0 Hz,
2H), 2.13 (m, 1H), 1.57 (m, 1H), 1.45–1.10 (m, 5H), 0.97 (d, J¼6.8 Hz,
3H), 0.83 (d, J¼6.8 Hz, 3H), 0.80 (s, 9H), 0.00 (s, 3H), ꢀ0.02 (s, 3H);
4.2.10. 3,7-Dihydroxy-4,8,10,14-tetramethyl-9-oxo-pentadeca-
10,12-dienoic acid methylester (14)
To a solution of 12 (123.3 mg, 0.172 mmol) in THF (1 mL) was
added TBAF (550 mL, 1 M in THF, 0.55 mmol) and the resulting
13C NMR (100 MHz, CDCl3)
d 177.6 (s), 140.1 (d), 116.5 (t), 74.6 (d),
72.9 (d), 44.1 (d), 39.0 (d), 37.8 (t), 31.9 (t), 28.5 (t), 25.7 (3q),18.0 (s),
16.3 (q), 13.9 (q), ꢀ4.6 (q), ꢀ4.8 (q); MS (EI) m/z: 269 [(MꢀH2Oꢀt-
Bu)þ, 19], 251 [(Mꢀ2H2Oꢀt-Bu)þ, 2], 157 (28), 139 (47), 95 (35), 75
(100). Anal. Calcd for C18H36O4Si: C, 62.74; H,10.53. Found: C, 62.44;
H, 10.54.
mixture was stirred for 3 days at rt. After hydrolysis with
a saturated NH4Cl aqueous solution (10 mL), the organic layer
was extracted with AcOEt (3ꢂ20 mL), dried over MgSO4, filtered,
and concentrated under vacuum. The residue was purified by
chromatography on silica gel (petroleum ether/AcOEt 6:4) to
afford product 14 (9.7 mg, 16%) as a colorless oil. Rf¼0.3 (pe-
4.3.2. (ꢀ)-4-[(tert-Butyldimethylsilyl)oxy]-5-methyl-8-(1-methyl-
allyl)oxocan-2-one (17)
To
a mixture of MNBA (203 mg, 0.58 mmol) and DMAP
troleum ether/AcOEt 6:4). 1H NMR (400 MHz, CDCl3)
d
6.98 (d,
(370 mg, 3.03 mmol) in toluene (100 mL), was added dropwise,
over a 30 min period, a solution of acid 16 (180 mg, 0.52 mmol) in
toluene (150 mL) then the resulting solution was stirred for 3 h at
rt. After hydrolysis with a saturated Na2CO3 aqueous solution
(150 mL), the organic layer was extracted with AcOEt (3ꢂ150 mL)
and the combined organic layers were washed with brine
(100 mL), dried over MgSO4, filtered, and concentrated under
vacuum. The residue was purified by chromatography on silica gel
J¼10.5 Hz, 1H), 6.33 (ddd, J¼15.0, 10.5, 1.0 Hz, 1H), 6.08 (dd,
J¼15.0, 7.0 Hz, 1H), 3.80 (m, 1H), 3.65 (s, 3H), 3.60 (m, 1H), 3.25
(m, 1H), 3.00–2.80 (m, 2H), 2.50–2.30 (m, 4H), 1.81 (s, 3H), 1.09
(d, J¼7.1 Hz, 3H), 1.01 (d, J¼6.7 Hz, 3H), 0.95–0.70 (m, 10H); 13C
NMR (100 MHz, CDCl3)
d 207.4 (s), 173.9 (s), 151.7 (d), 140.2 (d),
134.0 (s), 123.6 (d), 74.3 (d), 71.8 (d), 51.8 (q), 43.7 (d), 38.0 (d),
37.8 (t), 32.4 (t), 32.0 (d), 28.4 (t), 21.9 (q), 16.2 (q), 15.0 (q), 13.5
(q), 11.5 (q).
(petroleum ether/AcOEt 9:1) to afford lactone 17 (204 mg, 90%) as
20
a colorless oil. Rf¼0.6 (petroleum ether/AcOEt 9:1). [
(c 1.3, CHCl3). IR (neat) 2956, 2929, 2856, 1722 cmꢀ1
(400 MHz, CDCl3)
a
]
D
ꢀ58.6
4.2.11. 3-Hydoxy-6-[6-(2-hydroxy-3-methylbutyl)-3,5-dimethyl-4-
oxotetrahydropyran-2-yl]-4-methyl-hexanoic acid methylester (15)
To a solution of 13 (66 mg, 0.092 mmol) in THF was added HF$Py
;
1H NMR
d
5.77 (ddd, J¼14.6, 9.8, 7.9 Hz, 1H), 5.05–4.92
(m, 2H), 4.18 (ddd, J¼12.0, 5.0, 3.0 Hz 1H), 3.90 (td, J¼4.3, 1.3 Hz,
1H), 2.62 (d, J¼4.9 Hz, 2H), 2.33 (m, 1H), 1.87 (m, 1H), 1.76–1.42 (m,
4H), 1.03 (d, J¼7.1 Hz, 3H), 0.98 (d, J¼7.1 Hz, 3H), 0.86 (s, 9H), 0.13
(100 mL, 0.65 mmol) and the resulting mixture was stirred for 20 h
at rt. After hydrolysis with a saturated NaHCO3 aqueous solution,
the organic layer was extracted with AcOEt (3ꢂ20 mL), dried over
MgSO4, filtered, concentrated under vacuum, and the residue was
purified by flash chromatography on silica gel (CH2Cl2/MeOH 95:5)
to afford pyranone 15 (21.1 mg, 61%) as a non separable mixture of
diastereomers. Only the major diastereomer is reported. Rf¼0.6
(s, 3H), ꢀ0.01 (s, 3H); 13C NMR (100 MHz, CDCl3)
d 171.4 (s), 139.5
(d), 115.7 (t), 81.0 (d), 72.9 (d), 42.4 (d), 39.8 (t), 38.7 (d), 31.5 (t),
25.8 (4q), 23.4 (t), 18.1 (s), 16.3 (q), ꢀ4.1 (q), ꢀ5.0 (q); MS (EI) m/z:
326 (Mþ, 0), 269 [(Mꢀt-Bu)þ, 26], 251 [(Mꢀt-BuꢀH2O)þ, 8], 225
[(Mꢀt-BuꢀH2OꢀCCH2)þ, 12], 185 (59), 145 (38), 135 (49), 101 (56),
75 (100).
(CH2Cl2/MeOH 95:5). 1H NMR (400 MHz, CDCl3)
d 3.90–3.50 (m,
4H), 3.50 (s, 3H), 2.50–2.20 (m, 6H), 1.65–1.40 (m, 8H), 1.20–0.70
(m, 9H), 1.10 (d, J¼7.1 Hz, 3H), 0.98 (d, J¼6.8 Hz, 3H); 13C NMR
4.3.3. (ꢀ)-2-[6-(tert-Butyldimethylsilyl)oxy]-5-methyl-8-oxo-
oxocan-2-ylpropionaldehyde (18)
(100 MHz, CDCl3)
d 213.1 (s), 173.8 (s), 78.9 (d), 73.6 (d), 71.6 (d),
71.5 (d), 51.8 (q), 47.3 (d), 47.1 (d), 38.1 (t), 37.2 (t), 37.0 (d), 34.0 (d),
28.7 (t), 27.4 (t), 18.6 (q), 17.6 (q), 15.1 (q), 11.5 (q), 9.6 (q); MS (EI)
m/z: 311 (17), 171 (100).
To a solution of 16 (52 mg, 0.16 mmol) in a mixture of acetone/
H2O (2.5 mL/1 mL) were added NMO (0.11 g, 0.94 mmol) and OsO4
(2.5 mg, 0.01 mmol). The resulting mixture was stirred for 2 h at rt
then NaIO4 (0.2 g, 0.94 mmol) was added and the mixture was
stirred 5 min. After hydrolysis with a saturated NH4Cl aqueous
solution (50 mL), the organic layer was extracted with AcOEt
(3ꢂ50 mL) and the combined organic layers were washed with
brine, dried over MgSO4, filtered, and concentrated under vacuum
4.3. Second approach of octalactins
4.3.1. (þ)-3-[(tert-Butyldimethylsilyl)oxy]-7-hydroxy-4,8-
dimethyldec-9-enoic acid (16)
To
a
suspension of complex (S,S)-TaddolTiCpCl (1.52 g,
to give the unstable aldehyde 18 (52 mg, quantitative) as a brown
20
2.43 mmol) in Et2O (10 mL) at 0 ꢁC, was added crotylmagnesium
chloride (6.3 mL, 0.35 M in THF, 2.22 mmol). The resulting mixture
was stirred for 1 h at 0 ꢁC then cooled at ꢀ78 ꢁC and aldehyde 5
(564 mg, 1.86 mmol) was added to the mixture, which was allowed
oil. Rf¼0.6 (petroleum ether/AcOEt 8:2). [
a]
ꢀ54.6 (c 1.6, CHCl3).
D
IR (neat) 1721, 1461 cmꢀ1
;
1H NMR (400 MHz, CDCl3)
d 9.55 (d,
J¼1.5 Hz, 1H), 4.47 (ddd, J¼15.0, 7.1, 3.6 Hz, 1H), 3.78 (dapp, J¼6.8 Hz,
1H), 2.64–2.50 (m, 3H), 1.81 (m, 1H), 1.61–1.39 (m, 4H), 1.08 (d,

M.-T. Dinh et al. / Tetrahedron 64 (2008) 5703–5710
5709
J¼7.1 Hz, 3H), 0.99 (d, J¼7.1 Hz, 3H), 0.73 (s, 9H), 0.00 (s, 3H), ꢀ0.13
(s, 3H); 13C NMR (100 MHz, CDCl3)
202.4 (d), 170.8 (s), 76.8 (d),
72.7 (d), 50.6 (d), 39.7 (t), 38.5 (d), 31.4 (t), 25.8 (3q), 25.8 (d), 23.0
(t), 10.4 (q), 18.1 (s), ꢀ4.1 (q), ꢀ5.0 (q); MS (EI) m/z: 328 (Mþ, 0), 271
[(Mꢀt-Bu)þ, 12], 253 [(MꢀH2Oꢀt-Bu)þ, 5], 243 [(MꢀCOꢀt-Bu)þ,
12], 145 (46), 101 (61), 75 (100), 73 (53).
CDCl3) d 136.2 (d), 88.1 (s), 75.2 (d), 37.3 (t), 33.3 (d), 25.8 (3q), 22.7
d
(s), 18.1 (q), 17.8 (q), ꢀ4.4 (q), ꢀ4.6 (q); MS (EI) m/z: 386 (Mþ, 0), 343
(7), 329 (23), 257 (63), 203 (32), 187 (90), 139 (29), 73 (100).
4.3.7. (þ)-tert-Butyl-(1-isopropylpent-3-enyloxy)dimethylsilane (20)
To a solution of (73 mg, 0.189 mmol) in THF (2 mL) at ꢀ78 ꢁC
was added dropwise n-BuLi (200 mL, 2.52 M in hexanes, 0.50 mmol)
4.3.4. (ꢀ)-4-[(tert-Butyldimethylsilyl)oxy]-5-methylhex-1-ene (10)
and the resulting mixture was stirred at ꢀ78 ꢁC for 45 min. Then
To
a
suspension of complex (R,R)-TaddolTiCpCl (5.79 g,
MeI (60 mL, 0.964 mmol) was added dropwise and the mixture was
9.17 mmol) in Et2O (130 mL) at ꢀ40 ꢁC, was added allylmagnesium
chloride (5 mL, 2 M in THF, 10 mmol). After 1.5 h of stirring at 0 ꢁC,
the mixture was cooled at ꢀ78 ꢁC and isobutyraldehyde 8 (0.64 mL,
7.0 mmol) was added. The mixture was stirred for 3.5 h at ꢀ78 ꢁC
and then hydrolyzed with water (100 mL), with vigorous stirring at
rt overnight. After filtration of the mixture over Celite, the organic
layer was extracted with Et2O (3ꢂ100 mL) and the combined layers
were washed with brine (100 mL), dried over MgSO4, filtered, and
concentrated under vacuum. The residue was dissolved in CH2Cl2
(15 mL), then TBSCl (1.2 g, 8.4 mmol) and imidazole (953 mg,
14 mmol) were added. After 2 h of stirring at rt, the mixture was
hydrolyzed with water (100 mL) and the organic layer was extracted
with CH2Cl2 (3ꢂ100 mL). The combined layers were washed with
brine (100 mL), dried over MgSO4, filtered, and concentrated under
vacuum. The residue was purified by chromatography on silica gel
allowed to reach rt for 3 h. After hydrolysis with a saturated NH4Cl
aqueous solution (50 mL), the organic layer was extracted with
Et2O (3ꢂ50 mL), and the combined organic layers were washed
with brine (50 mL), dried over MgSO4, filtered, and concentrated
under vacuum. The residue was purified by chromatography on
silica gel (petroleum ether) to afford 20 (46 mg, 99%) as a colorless
20
oil. Rf¼0.8 (petroleum ether). [
a]
þ17.8 (c 0.03, CHCl3). IR (neat)
D
2956, 2928, 2856 cmꢀ1
;
1H NMR (400 MHz, CDCl3)
d 3.50 (tdapp,
J¼6.2, 3.6 Hz, 1H), 2.16 (m, 1H), 2.15 (m, 1H), 1.82 (m, 1H), 1.69 (t,
J¼2.6 Hz, 3H), 0.82 (s, 9H), 0.78 (d, J¼6.7 Hz, 3H), 0.76 (d, J¼4.8 Hz,
3H), 0.00 (s, 3H), ꢀ0.02 (s, 3H); 13C NMR (100 MHz, CDCl3)
d 76.8 (s),
76.7 (s), 75.7 (d), 32.2 (d), 25.8 (3q), 24.8 (t),19.1 (q),18.1 (s),16.1 (q),
3.5 (q), ꢀ4.3 (q), ꢀ4.7 (q); MS (EI) m/z: 240 (Mþ, 0), 183 (84), 111
(52), 73 (100). Anal. Calcd for C14H28OSi: C, 69.93; H,11.74. Found: C,
69.85; H, 11.74.
(petroleum ether/AcOEt 95:5) to afford alcohol 10 (1.2 g, 75% in 2
20
steps) as a yellow oil. Rf¼0.9 (petroleum ether/AcOEt 98:2). [
a
]
4.3.8. (ꢀ)-tert-Butyl-(4-iodo-1-isopropylpent-3-enyloxy)-
D
þ8.6 (c 1.6, CHCl3). IR (neat) 3080, 2920, 2820, 1640 cmꢀ1; 1H NMR
dimethylsilane (21)
(400 MHz, CDCl3)
d
5.78 (m, 1H), 5.03–4.94 (m, 2H), 3.44 (ddd,
To a suspension of Cp2ZrHCl (1.45 g, 5.61 mmol) in freshly and
degassed benzene (5 mL), was added dropwise at rt a solution of 20
(498 mg, 2.06 mmol) in benzene (5 mL). The resulting mixture was
stirred for 2 h at 40 ꢁC in darkness then cooled at 0 ꢁC and a solution
of I2 (1 g, 3.90 mmol) in THF (10 mL) was added dropwise. After
20 min of stirring at 0 ꢁC and hydrolysis by a saturated Na2S2O3
aqueous solution (50 mL), the mixture was stirred for 15 min at rt
then filtered over Celite. The organic layer was extracted with
AcOEt (3ꢂ50 mL) and the combined layers were washed with brine,
dried over MgSO4, filtered, and concentrated under vacuum. The
residue was purified by chromatography on silica gel (petroleum
J¼10.3, 5.8, 1.3 Hz, 1H), 2.16 (dtapp, J¼12.8, 1.1 Hz, 1H), 2.15 (dtapp
J¼5.8, 1.1 Hz, 1H), 1.65 (m, 1H), 0.86 (s, 9H), 0.86–0.81 (m, 6H), 0.01
(m, 6H); 13C NMR (100 MHz, CDCl3)
135.8 (d), 116.2 (t), 76.5 (d),
,
d
38.6 (t), 32.5 (d), 25.9 (3q), 18.6 (q), 18.5 (q), 18.3 (s), ꢀ4.2 (q), ꢀ5.2
(q); MS (EI) m/z: 228 (Mþ, 0), 187 (57), 171 (100), 99 (45), 73 (86).
4.3.5. (ꢀ)-3-[(tert-Butyldimethylsilyl)oxy]-4-methyl pentanal (11)9
A solution of 10 (397 mg, 1.73 mmol) in CH2Cl2 (10 mL) was
stirred under O3 bubbling at ꢀ78 ꢁC. After 15 min, PPh3 (0.4 g,
1.52 mmol) was added and the mixture was allowed to stir at rt for
2 h. After concentration under vacuum, the residue was purified by
flash chromatography on silica gel (petroleum ether/AcOEt 98:2) to
ether) affording vinyliodide 21 (198 mg, 26%) as a colorless oil.
20
Rf¼0.68 (petroleum ether). [
a]
ꢀ6.0 (c 1.8, CHCl3). IR (neat) 2955,
D
afford the unstable aldehyde 11 (397 mg, quantitative) as a color-
2927, 2855, 1678 cmꢀ1 1H NMR (400 MHz, CDCl3)
; d 6.15 (tapp,
20
less oil. Rf¼0.9 (petroleum ether/AcOEt 95:5). [
a
]
ꢀ15.4 (c 0.8,
J¼7.5 Hz, 1H), 3.46 (td, J¼6.9, 4.7 Hz, 1H), 2.35 (s, 3H), 2.17–2.04 (m,
2H), 1.68 (m, 1H), 0.86 (s, 9H), 0.86 (d, J¼8.6 Hz, 3H), 0.83 (d,
J¼6.0 Hz, 3H), 0.03 (s, 3H), 0.00 (s, 3H); 13C NMR (100 MHz, CDCl3)
D
CHCl3). IR (neat) 2950, 1720 cmꢀ1; 1H NMR (400 MHz, CDCl3)
d 9.77
(dd, J¼3.0, 1.9 Hz, 1H), 3.99 (dtapp, J¼7.1, 4.5 Hz, 1H), 2.49 (ddd,
J¼15.8, 7.1, 3.0 Hz, 1H), 2.38 (ddd, J¼15.8, 4.5, 1.9 Hz, 1H), 1.75 (m,
1H), 0.84 (d, J¼6.7 Hz, 3H), 0.83 (d, J¼6.7 Hz, 3H), 0.83 (s, 9H), 0.02
d
138.6 (d), 94.5 (s), 75.8 (d), 34.7 (t), 33.0 (d), 27.6 (q), 25.9 (3q),
18.7 (q), 18.1 (s), 17.4 (q), ꢀ4.2 (q), ꢀ4.6 (q); MS (EI) m/z: 368 (Mþ,
(s, 3H), 0.00 (s, 3H); 13C NMR (100 MHz, CDCl3)
d
202.6 (d), 72.4 (d),
0.5), 311 (45), 255 (45), 239 (24), 187 (100), 73 (78). Anal. Calcd for
47.2 (t), 34.0 (d), 25.7 (3q), 18.3 (q), 18.0 (s), 17.2 (q), ꢀ4.5 (q), ꢀ4.6
C14H29IOSi: C, 45.65; H, 7.94. Found: C, 46.08; H, 7.92.
(q); MS (EI) m/z: 230 (Mþ, 0), 173 (100), 129 (87), 101 (88).
4.3.9. (ꢀ)-4-[(tert-Butyldimethylsilyl)oxy]-8-{6-[(tert-butyl-
dimethylsilyl)oxy]-2-hydroxy-1,3,7-trimethyloct-3-enyl}-5-
methyloxocan-2-one (22)
4.3.6. (þ)-tert-Butyl-(4,4-dibromo-1-isopropylbut-3-enyloxy)-
dimethylsilane (19)
To a solution of PPh3 (660 mg, 2.51 mmol) in CH2Cl2 (4 mL) at
ꢀ78 ꢁC were added CBr4 (500 mg, 1.51 mmol) then a solution of
aldehyde 11 (200 mg, 0.94 mmol) in CH2Cl2 (1 mL). The resulting
stirring mixture was allowed to reach 0 ꢁC for 15 min then hydro-
lyzed with a saturated NaHCO3 aqueous solution (50 mL) and the
organic layer was extracted with CH2Cl2 (5ꢂ50 mL), washed with
brine (50 mL), dried over MgSO4, filtered, and concentrated under
vacuum. The residue was purified by flash chromatography on silica
To a solution of 20 (73.1 mg, 0.198 mmol) in Et2O (1 mL) at
ꢀ78 ꢁC was added dropwise t-BuLi (250
mL, 1.7 M in pentane,
0.425 mmol). The resulting solution was stirred for 30 min at
ꢀ78 ꢁC, then a solution of aldehyde 18 (61.2 mg, 0.186 mmol) in
Et2O (1 mL) was added dropwise. After stirring at ꢀ78 ꢁC for
45 min, the mixture was hydrolyzed with a saturated NH4Cl
aqueous solution (20 mL). The organic layer was extracted with
AcOEt (3ꢂ20 mL) and the combined organic layers were washed
with brine, dried over MgSO4, filtered, and concentrated under
vacuum. The residue was purified by chromatography on silica gel
(petroleum ether/AcOEt 8:2) affording product 22 (56 mg, 50%) as
gel (petroleum ether) to afford 19 (363 mg, 85%) as a colorless oil.
20
Rf¼0.9 (petroleum ether/AcOEt 98:2). [
a
]
þ0.45 (c 1.1, CHCl3). IR
D
(neat) 2955, 2927, 2855, 1462 cmꢀ1
;
1H NMR (400 MHz, CDCl3)
d
6.40 (t, J¼7.3 Hz, 1H), 3.48 (dd, J¼11.2, 5.0 Hz, 1H), 2.18 (dd, J¼7.3,
a mixture of diastereomers (1:3). Major diastereomer 22a: Rf¼0.2
20
6.4 Hz, 1H), 2.15 (dd, J¼6.4, 4.9 Hz, 1H), 1.62 (m, 1H), 0.83 (s, 9H),
(petroleum ether/AcOEt 9:1). [
a
]
ꢀ5.0 (c 0.8, CHCl3). IR (neat)
D
0.81 (d, J¼6.7 Hz, 6H), 0.00 (s, 3H), ꢀ0.01 (s, 3H); 13C NMR (100 MHz,
3460, 2955, 2925, 2854, 1786, 1715, 1251, 1185 cmꢀ1 1H NMR
;

5710
M.-T. Dinh et al. / Tetrahedron 64 (2008) 5703–5710
(400 MHz, CDCl3)
d
5.42 (tapp, J¼7.0 Hz, 1H), 4.36 (tdapp, J¼12.0,
(c 0.7, CHCl3). IR (neat) 3432, 2958, 2929, 2877, 1709, 1658 cmꢀ1; 1H
NMR (400 MHz, CDCl3)
3.7 Hz, 1H), 4.23 (br s, 1H), 3.91 (d, J¼6.4 Hz, 1H), 3.46 (m, 1H), 2.76
(dd, J¼12.8, 1.8 Hz, 1H), 2.61 (dd, J¼12.8, 6.7 Hz, 1H), 2.18–2.14 (m,
2H), 1.93 (m, 1H), 1.83 (m, 1H), 1.65–1.53 (m, 5H), 1.50 (s, 3H), 1.00
(d, J¼7.0 Hz, 3H), 0.87 (s, 9H), 0.85 (s, 9H), 0.83 (d, J¼6.8 Hz, 3H),
0.81 (d, J¼6.8 Hz, 3H), 0.72 (d, J¼7.0 Hz, 3H), 0.14 (2s, 6H), 0.01 (s,
3H), 0.00 (s, 3H), one OH does not appear in the spectrum; 13C NMR
d
6.80 (tapp, J¼7.0 Hz, 1H), 4.65 (tapp
,
J¼12.0 Hz, 1H), 3.97 (d, J¼6.1 Hz, 1H), 3.50–3.42 (m, 2H), 2.98 (dd,
J¼13.2, 1.7 Hz, 1H), 2.66 (dd, J¼13.2, 6.1 Hz, 1H), 2.41–2.30 (m, 2H),
2.10 (br s, 2H), 1.71 (s, 3H), 1.67–1.09 (m, 6H), 1.06 (d, J¼7.1 Hz, 3H),
0.98 (d, J¼7.1 Hz, 3H), 0.90 (d, J¼6.7 Hz, 3H), 0.89 (d, J¼6.8 Hz, 3H);
13C NMR (100 MHz, CDCl3)
d 203.3 (s), 172.7 (s), 141.5 (d), 137.4 (s),
(100 MHz, CDCl3)
74.1 (d), 72.6 (d), 40.1 (d), 39.7 (t), 38.7 (d), 32.4 (d), 32.3 (2t), 25.9
(3q), 25.8 (3q), 23.5 (t), 18.9 (q), 18.1 (2s), 16.9 (2q), 14.0 (q), 8.9 (q),
d
171.7 (s), 136.9 (s), 120.7 (d), 79.0 (d), 76.6 (d),
79.4 (d), 75.8 (d), 71.3 (d), 44.2 (d), 39.2 (t), 37.9 (d), 34.0 (t), 33.9 (d),
32.2 (t), 22.6 (t), 22.0 (q), 18.7 (q), 17.4 (q), 15.0 (q), 11.7 (q); MS (EI)
m/z: 340 (Mþ, 0), 279 (17), 207 (48), 167 (37), 149 (100). HRMS
calcd: 363.2147 [(MþNa)þ, M¼C19H32O5]; found: 363.2149.
ꢀ4.1 (2q), ꢀ4.6 (q), ꢀ5.0 (q). Minor diastereomer 22b: Rf¼0.4 (pe-
20
troleum ether/AcOEt 9:1). [
a
]
ꢀ28 (c 0.8, CHCl3). IR (neat) 3435,
D
2955, 2927, 2855, 1711, 1250, 1179 cmꢀ1; 1H NMR (400 MHz, CDCl3)
Acknowledgements
d
5.36 (tapp, J¼6.8 Hz, 1H), 4.70 (m, 1H), 3.90 (dapp, J¼6.6 Hz, 1H),
3.74 (d, J¼9.5 Hz,1H), 3.45 (m,1H), 2.75 (dd, J¼13.0,1.7 Hz,1H), 2.61
(m, 1H), 2.13 (tapp, J¼6.8 Hz, 2H), 2.00 (m, 1H), 1.89 (m, 1H), 1.70–
1.60 (m, 5H), 1.01–0.74 (m, 33H), 0.01–0.00 (m, 12H), one OH does
One of us (M.-T.D.) thanks Servier and the CNRS for a grant.
not appear in the spectrum; 13C NMR (100 MHz, CDCl3)
d 171.3 (s),
References and notes
136.6 (s), 125.9 (d), 80.5 (d), 77.6 (d), 76.5 (d), 72.6 (d), 40.1 (d),
39.9 (t), 38.5 (d), 32.6 (d), 32.3 (t), 28.3 (t), 26.1 (q), 25.9 (3q),
25.8 (3q), 23.0 (t), 18.7 (q), 18.1 (s), 18.0 (s), 17.0 (q), 11.3 (q), 10.9 (q),
ꢀ4.1 (2q), ꢀ4.6 (q), ꢀ5.0 (q). HRMS calcd: 593.4033 [(MþNa)þ,
M¼C31H62O5Si]; found: 593.4036.
1. Fenical, W.; Roman, M.; Tapiolas, D. M. J. Am. Chem. Soc. 1991, 113, 4682.
2. Buszek, K. R.; Sato, N.; Jeong, Y. J. Am. Chem. Soc. 1994, 116, 5511.
3. Total synthesis of (þ)-ent-octalactin A: McWilliams, J. C.; Clardy, J. J. Am. Chem.
Soc. 1994, 116, 8378.
4. (a) O’Sullivan, P. T.; Burh, W.; Fuhry, M. A. M.; Harrison, J. R.; Davies, J. E.; Feeder,
N.; Marshall, D. R.; Burton, J. W.; Holmes, A. B. J. Am. Chem. Soc. 2004, 126, 2194;
(b) Shiina, I.; Hashizume, M.; Yamai, Y.; Oshiumi, H.; Shimazaki, T.; Takasuma, Y.;
Ibuka, R. Chem.dEur. J. 2005, 11, 6601.
4.3.10. Octalactin B
To a solution of 22 (23.9 mg, 0.042 mmol) in CH2Cl2 (2 mL) was
added Dess–Martin periodinane (18 mg, 0.042 mmol) and the
resulting mixture was stirred for 1 h at rt. After hydrolysis with
a mixture of saturated NaHCO3/Na2S2O4 1:1 (20 mL/20 mL) aque-
ous solutions, the organic layer was extracted with CH2Cl2
(3ꢂ20 mL), and the combined organic layers were washed with
brine (20 mL), dried over MgSO4, filtered, and concentrated under
vacuum. The residue was dissolved in THF (3 mL) and to the
resulting solution was added HF$Py (0.25 mL, 0.25 mmol). After
20 h of stirring at rt, the mixture was hydrolyzed with water
(20 mL) and the organic layer was extracted with AcOEt (3ꢂ20 mL).
The combined organic layers were washed with brine, dried, fil-
tered, and concentrated. The residue was purified by preparative
5. (a) Buszek, K. R.; Jeong, Y. Tetrahedron Lett. 1995, 36, 7189; (b) Andrus, M. B.;
Argade, A. B. Tetrahedron Lett. 1996, 37, 5049; (c) Kodama, M.; Matsushita, M.;
Terada, Y.; Takeuchi, A.; Yoshio, S.; Fukuyama, Y. Chem. Lett. 1997, 117; (d) Inoue,
S.; Iwabuchi, Y.; Irie, H.; Hatakeyama, S. Synlett 1998, 735; (e) Garcia, J.; Bach, J.
Tetrahedron Lett. 1998, 39, 6761; (f) Bach, J.; Berenguer, R.; Garcia, J.; Vilarrasa.
Tetrahedron Lett. 1995, 36, 3425; (g) Hulme, A. N.; Howells, G. E. Tetrahedron Lett.
1997, 38, 8245; (h) Shimoma, F.; Kusaka, H.; Wada, K.; Azami, H.; Yasunami, M.;
Suzuki, T.; Hagiwara, H.; Ando, M. J. Org. Chem. 1998, 63, 920; (i) Harrison, J. R.;
Holmes, A. B.; Collins, I. Synlett 1999, 972; (j) Buszek, K. R.; Sato, N.; Jeong, Y.
Tetrahedron Lett. 2002, 43, 181.
6. (a) Shiina, I. Chem. Rev. 2007, 107, 239; (b) Aird, J. I.; Hulme, A. N.; White, J. W.
Org. Lett. 2007, 9, 631.
7. The diastereoselectivity and the enantioselectivity as well as the absolute con-
figuration of the stereogenic centers were determined by 1H NMR from the
corresponding mandelic esters, according to Trost, B. M.; Belletire, J. L.; Godleski,
S.; McDougal, P. G.; Balkovec, J. M. J. Org. Chem. 1986, 51, 2370.
8. The alcohol was previously prepared by Hafner, A.; Duthaler, R.; Marti, R.; Rihs,
G.; Rothe Streit, P.; Schwarzenbach, F. J. Am. Chem. Soc. 1992, 114, 2321.
9. Dinh, M.-T.; Bouzbouz, S.; Peglion, J.-L.; Cossy, J. Synlett 2005, 2851.
TLC (toluene/isopropyl alcohol 9:1), to afford octalactin B (9.8 mg,
20
68%) as a brown oil. Rf¼0.2 (petroleum ether/AcOEt 6:4). [
a]
ꢀ37
D